Allen M. Kaplan

Outcome of children with brain stem gliomas after treatment with 7800 cGy of hyperfractionated radiotherapy. A childrens cancer group phase 1/11 trial

Background. Brain stem gliomas remain the childhood brain tumors most resistant to treatment. Treatments with hyperfractionated radiotherapy at doses as high as 7560 cGy have been fairly well tolerated. This study was undertaken to determine the toxicity and possible efficacy of hyperfractionated radiotherapy in children with brain stem gliomas using 100 cGy of radiation twice daily, to a total dose of 7800 cGy.

Brainstem Gliomas in Children

Brainstem gliomas (BSG) with intrinsic and extensive brainstem involvement continue to have a poor outlook despite current treatment approaches. Neuroimaging studies have aided in the differentiation

Hyperfractionated radiation therapy (72 Gy) for children with brain stem gliomas A childrens cancer group phase I/II trial

Background. Most children with brain stem gliomas (BSG) die within 18 months of diagnosis. Early experience suggested that hyperfractionated radiation therapy (RT) at a dose of 72 Gy, administered in 1‐Gy fractions twice daily, possibly improved disease‐free survival for children with BSG.

High dose chemotherapy with autologous bone marrow rescue for children with diffuse pontine brain stem tumors

Purpose. Diffuse pontine tumors are highly lethal, and there are few long-term survivors with the standard treatment of external beam irradiation. We investigated the effectiveness of high-dose thiotepa and etoposide-based chemotherapy regimens with autologous bone marrow rescue (ABMR) in children with pontine tumors. Patients and methods. Sixteen children with diffuse pontine tumors were treated. Ten had resistant or recurrent tumors. All ten had previously received irradiation; five had also received chemotherapy and one, beta-interferon. Three high-dose chemotherapy regimens were employed. Six patients received three days of thiotepa (300 mg/m2/day) and etoposide (250–500 mg/m2/day) (TE); two received three days of carmustine (BCNU) (200 mg/m2/day divided every 12 hours) followed by TE (BTE); and two received three days of carboplatin (500 mg/m2/day) followed by TE (CTE). Six other patients had newly-diagnosed tumors and had not received any prior treatment. They all received the BTE regimen and subsequently were treated with hyperfractionated irradiation (7200–7800 cGy) beginning approximately six weeks post-ABMR. Results. There were two toxic deaths (13%), both in previously treated patients, due to multiorgan system failure and Candida septicemia in one case each. Median survival of the patients with resistant or recurrent disease was 4.7 months (range 0.1–18.7) from time of ABMR. Median survival of the newly-diagnosed patients was 11.4 months (range 7.6–17.1) from the time of ABMR. Conclusion. High-dose chemotherapy utilizing these regimens followed by ABMR did not appear to prolong survival compared to conventional therapy in these children with pontine tumors. Alternative strategies need to be developed for this highly lethal disease.

Use of Positron Emission Tomography for Presurgical Localization of Eloquent Brain Areas in Children with Seizures

Successful surgical management of a neoplastic or nonneoplastic seizure focus in close proximity to or within eloquent brain areas relies on precise delineation of the relationship between the lesion and functional brain areas. The aim of this series was to validate the usefulness and test the efficacy of noninvasive presurgical PET mapping of eloquent brain areas to predict surgical morbidity and outcome in children with seizures. To identify eloquent brain areas in 15 children (6 female and 9 male; mean age 11 years) with epileptogenic lesions PET images of regional cerebral blood flow were performed following the administration of [(15)O]water during motor, visual, articulation, and receptive language tasks. These images with coregistered magnetic resonance (MR) images were then used to delineate the anatomic relationship of a seizure focus to eloquent brain areas. Additional PET images using [18F]fluoro-2-deoxy-D-glucose (FDG) and [11C]methionine (CMET) were acquired to help localize the seizure focus, as well as characterize the lesion. Patient surgical management decisions were based on PET mapping in combination with coregistered MR images, PET-FDG findings, and the anatomic characteristics of the lesion. At follow-up 1-26 months after surgery, all patients that underwent temporal lobectomy (9 patients) and extratemporal resection (4 patients) for a neoplastic or nonneoplastic seizure focus are seizure-free with minimal postoperative morbidity. Of prime importance, no child sustained a postoperative speech or language deficit. PET imaging was also well tolerated without procedural complications. Based on PET mapping, a nonoperative approach was used for 2 children and a biopsy only was used in one child. When cortical injury involved prenatally determined eloquent cortex, PET demonstrated reorganization of language areas to new adjacent areas or even to the contralateral hemisphere. Integration of anatomical and functional data enhanced the surgical safety, defined optimal surgical approach, delineated the seizure focus from eloquent brain areas, facilitated maximum resection and optimized the timing of surgery, thereby minimizing surgical morbidity while maximizing surgical goals. PET measurements of FDG and CMET uptake were also helpful in localizing the seizure focus and grading the tumors. PET used for brain mapping in children provides the surgeon with strategic preoperative information not readily attainable with traditional invasive Wada testing or intraoperative cortical stimulation. PET mapping may also improve the outcome of extratemporal resections by allowing aggressive seizure focus resection. In addition, serial brain maps may optimize timing for surgical intervention by demonstrating reorganization of eloquent cortex often seen in younger children after cortical injury. Our results suggest that noninvasive presurgical brain mapping has the potential to reduce risk and improve neurologic outcome.

Primary amoebic meningoencephalitis with Naegleria fowleri: Clinical review

Two children with primary amoebic meningoencephalitis secondary to Naegleria fowleri are reported. Both children died, and the causative agent was identified at autopsy. Presentation and outcome conformed to the usual course of primary amoebic meningoencephalitis and reaffirm the gravity and rapid progression of this infection. The epidemiology, microbiology, diagnostic considerations, and treatment are discussed. Primary amoebic meningoencephalitis should be considered in the differential diagnosis of children with meningitis or encephalitis.

Positron Emission Tomography in Children With Neurofibromatosis-1

Neurofibromatosis-1 is an autosomal dominant genetic disorder commonly associated with neuropsychological complications. Focal areas of high signal intensity on magnetic resonance imaging (MRI) scans occur commonly but have shown inconsistent correlation with neuropsychological problems. Positron emission tomography (PET) scans utilizing [18F]fluoro-2-deoxy-D-glucose and MRI studies were performed on 10 children with neurofibromatosis-1 and multiple focal areas of high signal intensity to evaluate the regional cerebral metabolic rate for glucose of these lesions and other central nervous system structures. Co-registered PET and MRI studies confirmed reduced glucose metabolism of large focal areas of high signal intensity. Visual inspection and semiquantitative analysis of PET images demonstrated thalamic hypometabolism and varying degrees of cortical inhomogeneity in all cases of neurofibromatosis-1 compared to normal controls. Although a primary defect of the thalamus or cerebral cortex has not been defined, the metabolic abnormalities of this study suggest a potential relationship between these structures and the neuropsychological dysfunctions noted in neurofibromatosis-1. (J Child Neurol 1997; 12:499-506).

Hypomelanosis of Ito: Neurologic complications

Hypomelanosis of Ito is an uncommon, but clinically recognizable neurocutaneous syndrome. Neurologic complications are frequent and most commonly include seizures, psychomotor delays, changes in tone, and gait disturbances. Four patients with hypomelanosis of Ito and neurologic complications are presented; one patient had an associated chromosome aberration not reported previously.

Hemolytic uremic syndrome with particular involvement of basal ganglia and favorable outcome

Two children with hemolytic uremic syndrome and extrapyramidal complications are presented. Neuroimaging studies demonstrated bilateral basal ganglia (striatal) involvement with favorable recovery in both patients. The pathophysiology of the neurologic complications in hemolytic uremic syndrome are probably multifactorial. Our patients suggest a reversible process because both patients recovered clinically and radiographically. Neurologic complications do not always portend a poor prognosis and, in general, involvement of the basal ganglia is associated with favorable outcome.

Positron Emission Tomography Using [18F] Fluorodeoxyglucose and [ 11C] L-Methionine to Metabolically Characterize Dysembryoplastic Neuroepithelial Tumors

Dysembryoplastic neuroepithelial tumors are unique and benign congenital tumors occurring frequently in children and adolescents. Differentiation from other low-grade tumors is important for management. Five patients with confirmed dysembryoplastic neuroepithelial tumors were studied with positron emission tomography using glucose and protein metabolic uptake in an attempt to categorize these tumors metabolically. Functional brain mapping also was obtained to aid in operative management. Results of the study conclude that dysembryoplastic neuroepithelial tumors, although having similar neuroimgaing characteristics to other low-grade tumors, are distinguished by a unique metabolic profile. They are inactive tumors with no significant glucose or protein metabolic activity. The combination of preoperative positron emission tomographic metabolic studies with functional brain mapping allowed for prediction of tumor type, defined eloquent areas of cortical function, and improved approach and resection of the tumors with minimal risk of neurologic impairment. (J Child Neurol 1999;14:673-677).